Methods of producing pyrazole compounds

Abstract

The present invention is directed to methods of producing substituted pyrazole based compounds through novel intermediates and unique processes for preparing such intermediates which enables synthesis of final product through commercially viable route of synthesis. The present invention is also directed to novel methods of producing substituted pyrazole based thyroid like compounds, and solid forms of 3-{4-[(7-hydroxy-6-methyl-indan-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-1-yl}-propanoic acid, its pharmaceutical compositions, and methods of preparation thereof.

The invention claimed is: 
     
       1. A method for producing substituted pyrazole compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2  and R 3  are each independently selected from H, C 1-6  alkyl, C 1-6  alkoxy, or halogen; 
         R 4  is selected from H, C 1-10  saturated or unsaturated alkyl, C 1-10  substituted or unsubstituted arylalkyl, C 3-10  cycloalkyl, aryl, heteroaryl, C 1-10  alkyl silyl, C 1-10  alkyl silyl ethers, substituted or unsubstituted haloalkyl, or C 1-20  alkyl tricyclic; 
         n is 1 to 5; 
         or its pharmaceutically acceptable salts, solvates, co-crystals, and hydrates thereof; 
         comprising 
         condensing a compound of Formula (XIX), 
       
       
         
           
           
               
               
           
         
         wherein R 2 , R 3 , R 4  and n are as defined above; with a compound of Formula (XX), 
       
       
         
           
           
               
               
           
         
         wherein R is H or Pg 1 ; 
         wherein Pg 1  is hydroxy protecting group, and R 1  is as defined above; in the presence of a condensing agent to obtain a compound of Formula (VIIIa), 
       
       
         
           
           
               
               
           
         
         wherein R, R 1 , R 2 , R 3 , R 4  and n are as defined above; and optionally deprotecting and/or hydrolysing the compound of Formula (Villa) to yield substituted pyrazole compound of Formula (I). 
       
     
     
       2. The method according to  claim 1 , wherein the substituents R 2 , and R 3  are methyl; R 4  is H or C 1-6  alkyl; n is 2; and Pg 1  is methyl or benzyl. 
     
     
       3. The method according to  claim 1 , wherein the condensing agent is selected from the group comprising formaldehyde, paraformaldehyde, 1,3,5-trioxane, or mixtures thereof. 
     
     
       4. The method according to  claim 1 , wherein the condensation of a compound of Formula (XIX) with a compound of Formula (XX) is carried out optionally in the presence of acid catalyst selected from hydrochloric acid, sulphuric acid, p-toluenesulfonic acid, zinc chloride, or tin(II) chloride. 
     
     
       5. The method according to  claim 1 , wherein the condensation reaction is carried out in the presence of a solvent selected from acetic acid, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulphoxide, acetonitrile, N-methylpyrrolidone, cyclohexane, toluene, xylene or benzene. 
     
     
       6. The method according to  claim 1 , wherein the deprotection of a compound of Formula (VIIIa) is carried out in the presence of boron tribromide or palladium on carbon. 
     
     
       7. The method according to  claim 1 , wherein the hydrolysis of a compound of Formula (VIIIa) is carried out in the presence of a base selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, sodium bicarbonate, and potassium bicarbonate. 
     
     
       8. The method according to  claim 1 , wherein R is H.